Safety and Effectiveness of Tenofovir Gel in the Prevention of Human Immunodeficiency Virus (HIV-1) Infection in Women and the Effects of Tenofovir Gel on the Incidence of Herpes Simplex Virus (HSV-2) Infection

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The purpose of the study is to assess the safety and effectiveness of intravaginal 1% tenofovir gel in preventing Human Immunodeficiency Virus (HIV-1) infection and Herpes Simplex Virus (HSV-2) infection in sexually active women.

Condition or disease

Intervention/treatment

Phase

HIV Prevention

Drug: Tenofovir gelDrug: Universal placebo gel

Phase 3

Detailed Description:

This is a phase III, multicenter trial to assess the safety and effectiveness of 1% tenofovir gel, administered vaginally by approximately 2900 sexually active women at high risk for sexually transmitted HIV. Approximately 2600 women aged 18-30 years old will be enrolled to achieve the required number of endpoints to show an effect on HIV-1 infection, while up to 300 additional women aged 31-40 years old will be enrolled to collect more safety information in this age group.

This is an event driven study that plans to randomize seronegative women. Participants will be randomized to a 1:1 ratio to receive 1% tenofovir gel or placebo gel. Each will be asked to insert a dose of the assigned study product within 12 hours prior to a coital event and another dose as soon as possible within 12 hours after a coital event. Participants will be advised to use only two doses of gel in a 24 hour period.

All women will be evaluated for the rates of adverse events and the rate of HIV seroconversion. In addition, the study will evaluate several secondary endpoints that bear directly on potential risks and benefits of vaginal tenofovir gel use.

A Phase III, Multi-Centre, Randomized Controlled Trial to Assess the Safety and Effectiveness of the Vaginal Microbicide 1% Tenofovir Gel in the Prevention of Human Immunodeficiency Virus Type 1 Infection in Women, and to Examine Effects of the Microbicide on the Incidence of Herpes Simplex Virus Type 2 Infection

Participants will be required to insert a single dose of assigned gel intravaginally up to 12 hours before coitus and a second dose within 12 hours after coitus but no more than 2 applications within a 24 hour period.

Drug: Tenofovir gel

Tenofovir gel is a clear, transparent, viscous gel at concentrations of 1% formulated in purified water with edentate disodium, citric acid, glycerin, methylparaben, propylparaben, HEC, and pH adjusted to 4-5. Tenofovir gel will be supplies in a 4 ml single use applicator containing approximately 4 grams of gel, equivalent to approximately 40mg of tenofovir.

Placebo Comparator: Universal placebo gel

Participants will be required to insert a single dose of assigned gel intravaginally up to 12 hours before coitus and a second dose within 12 hours after coitus but no more than 2 applications within a 24 hour period.

Drug: Universal placebo gel

The placebo gel is an inert gel containing HEC as the gelling agent, purified water, sodium chloride, sorbic acid and sodium hydroxide. Each applicator contains approximately 4ml of placebo gel

Incidence of HIV-1 infection: HIV incidence will be determine by detection of HIV antibodies using two HIV rapid tests (of which one will be FDA approved) according to algorithm in protocol. One of the rapid tests will detect both HIV-1 and HIV-2; the other will be specific for HIV-1. All endpoints will be reviewed by an expert committee (the Endpoint Adjudication Committee). In carrying out this review, the Committee will use guidelines prepared by the protocol committee for this purpose and recorded in the Manual of Procedures

HSV-2 status will be established at enrollment according to a testing algorithm in the protocol. At product discontinuation samples of all those that were HSV-2 seronegative at enrollment will be tested. To identify and confirm incident HSV-2 infections and the timing of these infections, blood samples that were stored will be tested to determine the earliest equivocal or positive result. These samples will be then be tested by HSV Western blot. Samples positive on HSV Western blot will be deemed to be incident HSV-2 infections.

Pregnancy [ Time Frame: 30 months ]

Incidence of pregnancy loss, prematurity, low birth weight, and major and minor congenital anomalies will be determined

HIV testing will be conducted 3 months after product discontinuation and if HIV positive, the last stored sample will be tested to ascertain timing of infection and viral tenofovir resistance testing will be performed

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Layout table for eligibility information

Ages Eligible for Study:

18 Years to 40 Years (Adult)

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria:

Confirmed age 18-40 years (inclusive)

Able and willing to provide written informed consent

Able and willing to provide adequate locator information for study retention and safety purposes

Sexually active, defined as having had vaginal intercourse at least twice in the past 30 days prior to screening

HIV negative on two rapid tests performed by study staff within 30 days of enrolment (see algorithm in Appendix 3).

No evidence of glycosuria

No evidence of proteinuria greater than trace*

No history of pathological bone fractures

Have a negative pregnancy test

Women currently breastfeeding may be enrolled in the study

Agree to use a study-approved effective non-barrier form of contraception

Agree to adhere to study visits and procedures

Willing to use study gel as advised

Not using or taking any of the following groups of medications:

Nephrotoxic agents

Drugs that slow renal excretion

Immune system modulators

Other antiretrovirals

Exclusion Criteria:

History of adverse reaction to latex.

Plans any of the following during the study period

To travel away from the study site for more than 30 consecutive days.

To relocate away from the study site.

To become pregnant.

To enrol in any other study of an investigational product or behaviour modification related to HIV prevention.

If in the opinion of the examining clinician, is not sexually active

Inadequate renal function (serum creatinine greater than 1.5mg/dl and creatinine clearance less than 50ml/min, as estimated using the method of Cockcroft and Gault96 )

Has a clinically apparent finding on speculum pelvic examination (observed by study staff) involving deep epithelial disruption. Otherwise eligible participants with speculum pelvic examination findings involving deep epithelial disruption may proceed with enrolment after the findings have resolved and the inclusion/exclusion are met.

Received previously or receiving an experimental HIV vaccine

Currently participating in another HIV prevention intervention study or participation in any other clinical trial with a biomedical intervention in the last six months

Has current STI symptoms and/or other reproductive tract infection requiring treatment, as assessed by study staff. Otherwise eligible participants diagnosed during screening with infection(s) requiring treatment may be enrolled provided that treatment has been completed.

Any clinical evidence of untreated cervical abnormalities

Has any other condition that, based on the opinion of the Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.